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J. Biol. Chem., Vol. 279, Issue 28, 29670-29680, July 9, 2004

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Sequential Extracellular Matrix-focused and Baited-global Cluster Analysis of Serial Transcriptomic Profiles Identifies Candidate Modulators of Renal Tubulointerstitial Fibrosis in Murine Adriamycin-induced Nephropathy^*

Denise M. Sadlier, Susan B. Connolly, Niamh E. Kieran, Sarah Roxburgh, Derek P. Brazil, Lukas Kairaitis¶, Y. Wang¶, David C. H. Harris¶, Peter Doran, and Hugh R. Brady

From the Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Mater Misericordiae University Hospital and Dublin Molecular Medicine Centre, Dublin, Ireland and the ^¶Centre for Transplantation and Renal Research, The University of Sydney, Westmead Millenium Institute, New South Wales, Australia

Transcriptome analysis using microarray technology represents a powerful unbiased approach for delineating pathogenic mechanisms in disease. Here molecular mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring changes in the renal transcriptome in a glomerular disease-dependent model of TIF (adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with sequential primary biological function-focused and secondary "baited"-global cluster analysis of gene expression profiles. Primary cluster analysis focused on mRNAs encoding matrix proteins and modulators of matrix turnover as classified by Onto-Compare and Gene Ontology and identified both molecules and pathways already implicated in the pathogenesis of TIF (e.g. transforming growth factor 1-CTGF-fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC and Matrilin-2). Specific gene expression patterns identified by primary extracellular matrix-focused cluster analysis were then used as bioinformatic bait in secondary global clustering, with which to search the renal transcriptome for novel modulators of TIF. Among the genes clustering with ECM proteins in the latter analysis were endoglin, clusterin, and gelsolin. In several notable cases (e.g. claudin-1 and meprin-1) the pattern of gene expression identified in adriamycin nephropathy in vivo was replicated during transdifferentiation of renal tubule epithelial cells to a fibroblast-like phenotype in vitro on exposure to transforming growth factor- and epidermal growth factor suggesting a role in fibrogenesis. The further exploration of these complex gene networks should shed light on the core molecular pathways that underpin TIF in renal disease.

Received for publication, December 8, 2003 , and in revised form, March 16, 2004.

^* This work was supported by grants from the Irish Health Research Board (to H. R. B., S. B. C., and N. E. K.), the European Union (to H. R. B. and P. D.), and the Irish Programme for Research in Third Level Institutions. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Medicine and Therapeutics, Mater Misericordiae University Hospital, 44 Eccles St., Dublin 7, Ireland. E-mail: dsadlier.genome{at}mater.ie.

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